An injectable depot is designed to prolong the duration of action and reduce the frequency of injection for a drug. Such depots are generally administered by subcutaneous or intramuscular injection or by injection or instillation into body tissues, vessels or cavities. A depot prolongs the action of a pharmacologically active agent by releasing it into surrounding tissues from a reservoir slowly over time. A 1-day, 7-day or 30-day depot release profile, which enables a once-a-day, once-a-week or once-a-month injection schedule, respectively, would be highly desirable for convenience and better patient compliance.
Various materials have been employed for depot compositions. The most common depot-forming materials are biodegradable synthetic polymers, e.g., polylactic-co-glycolic acid (PLGA) and polylactic acid (PLA). The biodegradable polymer depot generally comes in two common forms: microcapsules/microspheres and polymer gels. The PLGA/PLA depots have been used in several FDA approved drugs i.e., Zoladex™ (goserelin acetate) and Lupron Depot™ (leuprolide acetate), which are PLGA microcapsules and microsphere, respectively. Eligard™ is in a polymer gel made by dissolving a drug and PLGA in a strong organic solvent i.e., N-methyl-2-pyrrolidone.
A major disadvantage of the polymer depots is that they require large diameter needles for injection or implantation due to the physical size of the microcapsules/microspheres and/or the high viscosity of the polymer gel. For example, 14- or 16-gauge (G) needles are required for implantation of Zoladex™ and 18 G or 20 G needles for injection of Eligard™. However, in common medical practice, needles of size greater than 21 G are generally not used for injection because they cause significant pain and psychological trauma for patients. For drugs like insulin, which are self-administered daily, fine 25-27 G needles and 1 cc syringes are used. The injectability or ease with which the end user can self-inject through such a system will be key to such a drug's user compliance and therapeutic efficacy. For discussion purposes herein, the injectability of a syringe-administered depot is quantitatively defined as meeting the “Acceptable Injectability Criterion” if it requires an applied force of no more than 10 pounds to be extruded from a 1 cc syringe through a 25 G ½ inch long needle at rate of 2 cc/min. Such a scenario represents typical conditions during the self-administration of insulin and other self-injected drugs.
Moreover, PLGA and PLA are insoluble in water and both require extremely strong organic solvents such as methylene chloride, chloroform or N-methyl-2-pyrrolidone to fabricate the microcapsules/microspheres or gels. Unfortunately, most biological molecules such as protein drugs are incompatible with strong solvents. Methylene chloride or N-methyl-2-pyrrolidone, which are used in PLGA/PLA production, denature insulin immediately upon contact.
Phospholipids (PL) are naturally occurring substances in the human body and are the major constituents of cell membranes. These molecules have an established record of safety and biocompatibility as components in injected medicines. PL are also generally insoluble in water (like the PLGA polymers) and following injection into tissue and coming into contact with aqueous body fluids and tissues, PL can precipitate and trap a co-administered drug, to form a drug-PL co-precipitate that can function as a depot. Over time, this mass diffuses slowly into a surrounding tissue and/or is degraded by phospholipase, which is an enzyme distributed throughout the body that slowly hydrolyzes phospholipids, resulting in a slow release of the trapped drug. With such favorable safety, solubility and biocompatibility properties, it would appear that phospholipids are ideal depot materials. However, to date, there has been few successful depot drug product based on phospholipids. One primary problem is the poor injectability associated with phospholipid-based compositions.
This inventor has discovered that a high concentration (i.e., 20-80%) of phospholipids is generally required in order to form the mass that permits depot functionality. However, once the phospholipid concentration exceeds about 20% in a composition, the composition becomes thick, viscous and difficult to inject through fine needles without using an excessively high force. For example, Phosal 50PG, Phosal 50SA, and Phosal 50MCT (produced by the America Lecithin Company) are liposome-forming compositions containing about 50% phospholipids dissolved in propylene glycol/ethanol, oil, and medium chain oil, respectively. With their honey-like consistency, the Phosal compositions are very difficult to inject using a conventional hypodermic needle and syringe. It requires more than 20 pounds of force to extrude Phosal through a 25 G ½ inch long needle from a 1 cc syringe at a plunger speed of 2 cc/min. Thus, it will take 2-5 minutes or more to manually extrude 1 mL of the Phosal-based depot through a 26 G needle even using a very high force—which is impractical for general medical use and definitely not suitable for self-administration. Therefore, acceptable injectability using fine hyperdermic needles has been a main reason preventing phospholipids from becoming useful depot materials. This invention discloses phospholipid depots with surprisingly good injectability that meets the Acceptable Injectability Criterion, as defined above.
Another difficulty working with phospholipids is that phospholipids are only soluble in certain organic solvents (e.g., ethanol) or oil (e.g., vegetable oil) and many drugs (such as insulin or other protein drugs) are only soluble and stable in water, but not soluble or stable in solvents or oils that can dissolve phospholipids. Therefore, it has been impossible to manufacture phospholipid-based depots using conventional solvent methods or other methods disclosed in prior art without having the solvent-sensitive drugs precipitate or degrade (See WO 2006/002050, U.S. Pat. No. 5,807,573, WO/1994/008623, U.S. Pat. No. 5,004,611 and Harry Tiemesseen, et al. (2004) European Journal of Pharmaceutics and Biopharmaceutics Volume 58 (2005), pp 587-593).
Another hurdle in the production of phospholipid depots relates to difficulty in preparing a depot suitable for injection under sterile conditions. Many drugs are heat-sensitive and cannot survive heat sterilization (e.g., autoclaving) or radiation sterilization. This is especially true for biological drugs such as insulin and other protein drugs. In many cases, the only practical way to sterilize a protein-containing composition is by filtration through a 0.2- or 0.45-micron pore membrane to remove any microbial contaminants. With a 20-80% phospholipid content, the thick consistency of the depot compositions precludes any possibility of sterilization by filtration. Therefore, this invention also teaches unique methods for preparing depots that may be sterilized by filtration.
Insulin is the mainstay for treatment of virtually all type 1 and many type 2 diabetic patients. Insulins and insulin formulations are divided into two types: (1) quick onset/short acting and (2) long-acting. The first type (“preprandial”) is used to control transient elevated blood glucose levels that occur after meals. Long-acting insulin is used to maintain a controlled baseline level of glucose level over a long duration such as 12-24 hours. A long-acting insulin or insulin formulation is thus referred to as “basal insulin.”
Basal insulin therapy is utilized to achieve “glycemic control,” which is the maintenance of blood glucose levels at a constant and acceptable level without fluctuations. Sufficient glycemic control requires plasma glucose levels to be maintained within normal limits (70-130 mg/dl, or 3.9-7.2 mmol/L) and indistinguishable from that in a non-diabetic person. Glucose level fluctuations, especially the high peaks and valleys resulting from poor glycemic control, are high risk factors for diabetes-associated complications that can lead to morbidity and mortality. Therefore, to achieve adequate glycemic control, an ideal basal insulin formulation should deliver insulin to the circulation at a constant rate (i.e., peak-less) over a prolonged period of time, such as 24 hours. Human insulin itself has a rapid onset and short duration of action (the half-life of insulin is only about 5-6 minutes in the circulation). Therefore, a human insulin depot formulation requires an approach that is capable of both sequestering and releasing it slowly and constantly to address the requirements needed for a successful basal insulin therapy.
The pharmacological efficacy of insulin can be readily monitored by following the post-administration plasma glucose concentration-time profile and the plasma insulin concentration-time profile. The former measures insulin's glucose-lowering efficacy or the pharmacodynamic or PD profile and the latter measures the insulin plasma levels as a pharmacokinetic or PK profile.
The currently available basal human insulin formulations in the US include the NPH (Neutral Protamine Hagedorn) insulin sold under the trade names of HUMULIN® N and NOVOLIN® N by Eli Lilly and Company and Novo Nordisk, respectively. NPH insulin, which was invented in the 1930's by Hans Christian Hagedorn, is a suspension of zinc-insulin crystalline complexes combined with the positively charged polypeptide, protamine. The complexation with zinc and protamine turns the insulin into insoluble particles after injection that slowly release insulin.
Despite its long history of use (over 70 years), NPH is not an ideal depot formulation for basal insulin therapy. The following shortcomings are well known:                High Cmax: The NPH PK profile has a pronounced peak or Cmax that occurs in about 4 hours after subcutaneous injection. This high Cmax causes hypoglcermia. Since basal insulin is typically given at bedtime, the 4 hr post-injection hypoglycemic phase normally occurs when the patient is asleep. However, if the patient were to awaken in the middle of the night and get out of bed, the hypoglycemic episode could lead to fainting.        Short duration of action: NPH releases a substantial amount of its insulin within the first few hours and is depleted in about 14-16 hours, making it suitable only as a twice-a-day (BID) formulation. This deficiency disqualifies NPH as a true, once-a-day (QD) formulation.        High peak-to-valley ratio of plasma insulin: In clinical practice, BID regimens for NPH are still unable to stem high Cmax (peak) and low Cmin (valley) fluctuations. The resulting sub-optimal glycemic control increases the risk for diabetic complications.        Poor dose uniformity: For suspensions like NPH, an intrinsic problem is the inability to achieve uniform injection-to-injection dosing in a small volumes—even with strict adherence to the rigorous pre-injection mixing/shaking instructions. For NPH this difficulty is further compounded because it is typically injected in very small volumes (<1 mL). Thus, the variability with respect to the amount of insulin injected dose-to-dose for NPH can be as high as 10-20%, which also contributes to poor glycemic control.        
More recently, two basal insulin drugs, LANTUS® (insulin glargine, Sanofi-aventis) and LEVEMIR® (insulin detemir, Novo Nordisk), were developed and subsequently approved. Both LANTUS® and LEVEMIR® are insulin analogs, in that they are chemically modified insulin and are not the authentic human insulin molecule. In contrast to NPH, LANTUS® releases insulin in a “peak-less” (peak to trough ratio less than 5 within 24 hours after each injection) PK profile over 24 hours, which are key factors underlying the drug's applicability as a once-a-day dose and its achievement of better glycemic control. Compared to NPH, LEVEMIR® has a less spiky PK profile but its duration of action is somewhat similar to NPH, making it suitable only for BID dosing. Of these two basal insulin analogs, LANTUS® has clear advantages over NPH owing to its 24 hr peak-less insulin PK profile.
Recently, LANTUS® has been reportedly linked to certain cancers. The FDA noted: “3 of 4 observational studies suggest an increased risk for cancer associated with use of LANTUS®.” (Pink Sheet, Jul. 6, 2009, p. 30). LANTUS® is also associated with a high incidence of injection site pain possibly due to its low pH formulation (pH 4). Unlike human insulin, the long-term safety of the insulin analogs are unclear.
Despite the recent advances for insulin drugs, there is a need for improved basal insulin formulations that provide a 24 hr peak-less PK profile. Moreover, there remains a need for a phospholipid depot suitable for injection under sterile conditions. A method is needed to enable a water-soluble or solvent-incompatible drug to be incorporated into a phospholipid depot. The present invention satisfies these and other needs.